Imaging and therapy of intrauterine inflammation induced perinatal brain injury

描述（由申请人提供）：已知宫内炎症是心室周围白质软化症（PVL）的危险因素之一，PVL随后导致脑瘫的发展。近年来，小胶质细胞的活化与PVL的发展有关。这项研究的长期目标是了解在发育过程中导致脑损伤的细胞和代谢紊乱，并利用这些信息设计特异性的、有针对性的治疗方法来预防脑损伤。核心假设是内毒素诱导的宫内炎症导致胎儿大脑小胶质细胞的激活，随着时间的推移导致少突胶质细胞损伤和白质损伤，而减少小胶质细胞激活的时间过程将阻止这种损伤。这一假设将在兔宫内炎症模型中进行验证，具体目的如下：(1)通过评估PET示踪剂[C-11] PK11195的摄取变化、组织学上的小胶质细胞数量和少突胶质细胞损失、弥散张量成像和神经行为变化，确定暴露于宫内炎症的幼兔新生脑中的小胶质反应和白质损伤。(2)通过对宫内内毒素暴露幼兔的[C-11] PK11195摄取、弥散张量成像和神经行为评分的纵向测量，确定米诺环素产后抗炎治疗是否能缩短宫内炎症暴露新生兔的小胶质细胞激活时间，减轻脑损伤，改善神经行为结局。我们期望这项研究能够更好地理解小胶质细胞激活的时间和空间进展及其与发育中的大脑白质损伤的关系，使用新的非侵入性神经成像技术，可以转化为临床环境，并可用于跟踪损伤和对治疗的反应。该建议的培训目标是作为一名具有应用神经影像学评估围产期脑损伤新药物治疗专业知识的儿科神经强化医师，实现调查独立性。教育方面包括在正电子发射断层扫描（PET）神经成像领域的监督研究和分析，开发动物模型，免疫组织化学和炎症标记物的识别，以及生物统计学和研究伦理行为方面的正式结构化培训。

DESCRIPTION (provided by applicant): Intrauterine inflammation is known to be one of the risk factors for periventricular leukomalacia (PVL) that subsequently leads to the development of cerebral palsy. In recent years, microglial cell activation has been implicated in the development of PVL. The long term goal of this study is to understand the cellular and metabolic derangements leading to brain injury during development and use this information to design specific, targeted therapy to prevent the brain injury. The central hypothesis is that endotoxin induced intrauterine inflammation leads to activation of microglial cells in the fetal brain that progresses over time leading to oligodendrocyte damage and white matter injury, and that decreasing the time course of microglial activation will arrest this injury. This hypothesis will be tested in a rabbit model of intrauterine inflammation, by pursuing the following specific aims: (1) Determine the microglial response and white matter injury in the newborn rabbit brain in pups exposed to intrauterine inflammation by assessing changes in uptake of the PET tracer [C-11] PK11195, by microglial numbers and oligodendrocyte loss on histology, by diffusion tensor imaging, and by neurobehavioral changes. (2) Determine whether postnatal anti- inflammatory treatment with minocycline can decrease the time course of microglial cell activation, diminish brain injury and improve neurobehavioral outcome in the neonatal rabbit exposed to intrauterine inflammation as assessed by longitudinal measurements of [C-11] PK11195 uptake, diffusion tensor imaging and neurobehavioral scores in the newborn rabbit brain in pups exposed to endotoxin in utero. We expect that this research will lead to better understanding of the temporal and spatial progression of microglial activation and its relationship to white matter injury in the developing brain using novel non- invasive neuroimaging techniques that can be translated to the clinical setting and can be used to follow the injury and response to therapy. The training objective of this proposal is to achieve investigative independence as a pediatric neurointensivist with expertise in the application of neuroimaging for assessing novel drug therapies in perinatal brain injury. The educational aspect involves supervised research and analyses in the area of neuroimaging with Positron Emission Tomography (PET), in developing the animal model, immunohistochemistry and identification of inflammatory markers and formal, structured training in biostatistics and the ethical conduct of research.